SB‐224289–a novel selective (human) 5‐HT_1B receptor antagonist with negative intrinsic activity

Abstract

1 Human 5-HT 1B (h5-HT 1B ) and human 5-HT 1D (h5-HT 1D ) receptors show remarkably similar pharmacology with few compounds discriminating the receptors. We report here on a novel compound, SB-224289 (1'-Methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3-f]indole-3,4'-piperidine] oxalate), which has high a nity for h5-HT 1B receptors (pK 1 =8.16+0.06) and displays over 75 fold selectivity for the h5-HT 1B receptor over all other 5-HT receptors including the h5-HT 1D receptor and all other receptors tested thus far. 2 Functional activity of SB-224289 was measured in a [ 35 S]GTPgS binding assay on recombinant h5-HT 1B and h5-HT 1D receptors expressed in Chinese Hamster Ovary (CHO) cells. SB-224289 displayed negative intrinsic activity at both receptors with higher potency at h5-HT 1B receptors. SB-224289 caused a rightward shift of agonist concentration response curves consistent with competitive antagonism and generated a nities comparable with those obtained from competition radioligand receptor binding studies. 3 SB-224289 potentiated [ 3 H]5-HT release from electrically stimulated guinea-pig cerebral cortical slices to the same extent as as the non-selective 5-HT 1 antagonist methiothepin. SB-224289 also fully reversed the inhibitory e ect of exogenously superfused 5-HT on electrically stimulated release. 4 Using SB-224289 as a tool compound, we con®rm that in guinea-pig cerebral cortex the terminal 5-HT autoreceptor is of the 5-HT 1B subtype.

Molecular cloning, sequence analysis and pharmacological properties of the porcine 5‐HT1D receptor

“…However, it is interesting to point out that the selective antagonist at the human 5-HT 1D receptor, BRL15572 Schlicker et al, 1997), displayed much less a nity at the pig 5-HT 1D receptor ( Figure 5, upper panels). As can be expected, the selective antagonist at the human 5-HT 1B receptor, SB224289 Selkirk et al, 1998), did not show a high a nity at the pig 5-HT 1D receptor ( Figure 5, lower panels).…”

“…, that have been shown to be selective antagonists for the human 5-HT 1B and 5-HT 1D receptors Schlicker et al, 1997;Gaster et al, 1998;Selkirk et al, 1998), respectively, it is di cult to be sure that these compounds also have a high and selective a nity at the respective porcine receptor.…”

Dehydrogenation of Indoline by Cytochrome P450 Enzymes: A Novel “Aromatase” Process

“…Indolines have been widely investigated as serotonin receptor agonists or antagonists. Examples include: SB-242084, a selective 5-HT 2C receptor antagonist with anxiolytic activity (Bromidge et al, 1997); SB-224289, a selective 5-HT 1B receptor antagonist with negative intrinsic activity (Selkirk et al, 1998); and 1-(1-indolinyl)-2-propylamine, a 5-HT 2C receptor agonist for the treatment of obesity (Bentley et al, 2004). A series of potent factor Xa inhibitors, the indoline derivatives of DX-9065a, could be novel antithrombotics for the treatment and prevention of thromboembolic diseases .…”

Constitutively active Gq/11-coupled Receptors Enable Signaling by Co-expressed Gi/o-coupled Receptors

“…Co-expression of 5-HT 1B R together with H 1 R resulted in a significantly increased constitutive activation of NF-B (Figs. 2 and 3), which was completely inhibited by the inverse H 1 R agonist mepyramine but also, partially, by the inverse 5-HT 1B R agonist SB-224289 (28). This inverse 5-HT 1B R agonist inhibited only the increased constitutive NF-B activation that is observed upon co-expression of the 5-HT 1B R but not the constitutive H 1 R-mediated NF-B activation (Fig.…”